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Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.
Front Immunol. 2020; 11:699.FI

Abstract

TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24-48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1-2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM.

Authors+Show Affiliations

Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Transfusion Unit, Department of Laboratories, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Radiology and Radiotherapy, Sapienza University, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Stem Cell Laboratory and Cell Therapy Center, Giannina Gaslini Institute (IRCCS), Genoa, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy. Sapienza, University of Rome, Rome, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32477328

Citation

Merli, Pietro, et al. "Immune Modulation Properties of Zoledronic Acid On TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: an Analysis On 46 Pediatric Patients Affected By Acute Leukemia." Frontiers in Immunology, vol. 11, 2020, p. 699.
Merli P, Algeri M, Galaverna F, et al. Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. Front Immunol. 2020;11:699.
Merli, P., Algeri, M., Galaverna, F., Milano, G. M., Bertaina, V., Biagini, S., Girolami, E., Palumbo, G., Sinibaldi, M., Becilli, M., Leone, G., Boccieri, E., Grapulin, L., Gaspari, S., Airoldi, I., Strocchio, L., Pagliara, D., & Locatelli, F. (2020). Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. Frontiers in Immunology, 11, 699. https://doi.org/10.3389/fimmu.2020.00699
Merli P, et al. Immune Modulation Properties of Zoledronic Acid On TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: an Analysis On 46 Pediatric Patients Affected By Acute Leukemia. Front Immunol. 2020;11:699. PubMed PMID: 32477328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. AU - Merli,Pietro, AU - Algeri,Mattia, AU - Galaverna,Federica, AU - Milano,Giuseppe Maria, AU - Bertaina,Valentina, AU - Biagini,Simone, AU - Girolami,Elia, AU - Palumbo,Giuseppe, AU - Sinibaldi,Matilde, AU - Becilli,Marco, AU - Leone,Giovanna, AU - Boccieri,Emilia, AU - Grapulin,Lavinia, AU - Gaspari,Stefania, AU - Airoldi,Irma, AU - Strocchio,Luisa, AU - Pagliara,Daria, AU - Locatelli,Franco, Y1 - 2020/05/12/ PY - 2020/02/19/received PY - 2020/03/27/accepted PY - 2020/6/2/entrez PY - 2020/6/2/pubmed PY - 2020/6/2/medline KW - TcRαβ/CD19 cell depleted haploidentical stem cell transplantation KW - TcRγδ+ lymphocytes KW - acute leukemia KW - children KW - zoledronic acid SP - 699 EP - 699 JF - Frontiers in immunology JO - Front Immunol VL - 11 N2 - TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24-48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1-2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/32477328/Immune_Modulation_Properties_of_Zoledronic_Acid_on_TcRγδ_T-Lymphocytes_After_TcRαβ/CD19-Depleted_Haploidentical_Stem_Cell_Transplantation:_An_analysis_on_46_Pediatric_Patients_Affected_by_Acute_Leukemia L2 - https://doi.org/10.3389/fimmu.2020.00699 DB - PRIME DP - Unbound Medicine ER -
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